Multiple Clinical Phenotypes Research Articles

Cluster analysis identifies a pathophysiologically distinct subpopulation with increased serum leptin levels and severe obstructive sleep apnea

PurposeTo investigate the different pathophysiologies of obstructive sleep apnea (OSA) phenotypes using cluster analysis. Differences between leptin/adiponectin levels in the resulting OSA phenotypes were also examined.MethodsIn total, 1057 OSA patients were selected, and a retrospective survey of clinical records, polysomnography results, and blood gas data was conducted. Patients were grouped into four clusters by their OSA severity, PaCO2, body mass index (BMI), and sleepiness. A k-means cluster analysis was performed, resulting in a division into four subpopulations. The Tukey or Games-Howell tests were used for intergroup comparisons.ResultsAmong the 20 clinical OSA items, four common factors (Epworth Sleepiness Scale [ESS], BMI, Apnea-Hypopnea Index [AHI], and PaCO2) were extracted by principal component analysis, and a cluster analysis was performed using the k-means method, resulting in four distinct phenotypes. The Clusters 1 (middle age, symptomatic severe OSA) and 4 (young, obese, symptomatic very severe OSA) exhibited high leptin levels. C-reactive protein levels were also elevated in Cluster 4, indicating a different pathophysiological background. No apparent differences between clusters were observed regarding adiponectin/leptin ratios and adiponectin levels. Classification into groups based on phenotype showed that Epworth Sleepiness Scale [ESS] score and disease severity were not correlated, suggesting that sleepiness is affected by multiple elements.ConclusionsThe existence of multiple clinical phenotypes suggests that different pathophysiological backgrounds exist such as systemic inflammation and metabolic disorder. This classification may be used to determine the efficacy of continuous positive airway pressure treatment that cannot be determined by the AHI.

Pediatric use of omalizumab for allergic asthma

ABSTRACT Introduction Severe pediatric asthma is associated with significant morbidity as well as with a high economic burden. It represents a heterogeneous disease with multiple clinical phenotypes. Currently, physicians are facing the challenge to provide a ‘personalized medicine approach’, which is tailored to the diverse pathomechanisms underlying clinical presentations. Three main endotypes of airway inflammation have been described in children with severe asthma. While neutrophilic and paucigranulocytic inflammatory patterns are quite uncommon in childhood, type Th2 inflammation asthma with elevated IgE is the most prevalent in pediatric asthma. Considering the pivotal role of IgE in type Th2 inflammation asthma, the blockade of IgE using anti-IgE therapy represents a potent therapeutic option for severe pediatric asthma in children. Areas covered This review aims to focus on the role of omalizumab as a treatment option in pediatric patients (aged six years and above) with severe allergic asthma. Expert opinion The clinical efficacy and safety of omalizumab for the treatment of pediatric asthma is well documented in clinical trials and observational studies. Further studies are still required to characterize the potential benefit of anti-IgE therapy in airway remodeling, identify additional biomarkers of clinical response and address current unmet needs, including the limit on omalizumab use in children younger than six years.

BRIDGING THE GAP BETWEEN NEUROLOGY AND PSYCHIATRY- PSYCHIATRIC SYMPTOMS IN THE COURSE OF NEURODEGENERATIVE DISORDERS

It is increasingly recognized that there is significant heterogeneity in phenotype and clinical trajectories in Alzheimer's disease as well as Lewy Body and Vascular dementia. Relatively common neurodegenerative disorder, Lewy Body Dementia (LBD) presents with psychiatric features. Mood disorders are common and often precede core symptoms of LBD. Patient with LBD especially early in the course of disease are at increased risk for suicide. Psychosis is one of the most debilitating symptoms of LBD as it is an independent risk factor for nursing home placements, increased caregiver distress and mortality. Visual hallucinations are the most common psychotic manifestation in LBD. Auditory, olfactory, tactile and gustatory hallucinations and delusions are less frequently found. Global cognitive deficits including attention, frontal executive dysfunction, visuospatial abnormalities, language and verbal memory were associated with the presence of psychosis in Lewy Body Dementia. Glucocerebrosidase gene (GBA) mutations and polymorphisms found to be associated with LBD. Up to 25% of Alzheimer's disease (AD) cases do not show the typical neuropathology. Subtypes and atypical non-amnestic AD presentations have been formalized in the International Working Group (IWG) clinical diagnosis criteria. Frontal signs and symptoms are often seen in Alzheimer's disease especially in patients with early onset. In those clinical situations differential diagnosis especially distunguising between Clinical diagnosis of atypical AD has significantly been improved by the availability of biomarkers, including cerebrospinal fluid levels of Aβ42, total tau and phosphorylated tau181. MRI volumetric estimation of hippocampal and medial temporal atrophy, and amyloid brain PET imaging. We will review atypical forms of AD from these varied perspectives to help improve diagnostic confidence among clinicians. Cerebral amyloid angiopathy (CAA) is a highly prevalent pathologic finding in the elderly contributing to cognitive loss, neuropsychiatric symptoms and morbidity. It is characterized by predominantly vascular deposition of beta amyloid protein Its prevalence varies across different populations. Initially conceptualized as vascular dementia syndrome CAA was proved to overlap with AD pathology and is thought to affect over 80% of AD patients. Lobar intracerebral hemorrhage and infarction are the well-known striking clinical manifestations, but CAA has multiple other clinical phenotypes: Inflammatory disease in the form of vasculitis known as amyloid beta related angiitis (ABRA) and inflammatory leukoencephalopathy, also known as CAA related inflammation (CAA-RI). Due to multiple clinical phenotypes CAA remains clinically underdiagnosed and underreported especially in elderly with dementia and other psychiatric symptoms. The underlying pathophysiological mechanism for the spectrum of CAA will be discussed

Medicina de precisión en sepsis: utilidad de los biomarcadores en pacientes biomarcadores en pacientes críticamente enfermos

Durante años la evolución del cuidado intensivo ha intentado ofrecer una atención basada en protocolos y paquetes de manejo agrupados por patologías y cuadro sindromáticos. Aunque se logró disminuir la mortalidad en diferentes patologías (sepsis y síndromes coronario agudo y de distrés respiratorio agudo), no se han resuelto por completo los problemas clínicos, en especial el diagnóstico y el manejo. Una nueva opción ha surgido en el horizonte denominada “medicina de precisión”, entendida como estrategia de prevención y tratamiento que tiene en cuenta la variabilidad individual. La sepsis es un síndrome con múltiples aristas en cuanto al fenotipo y genotipo, cuyo diagnóstico temprano es relevante para los desenlaces clínicos. Hasta el momento el enfoque principal ha sido la identificación de un germen etiológico para diferenciarla del síndrome de respuesta inflamatoria sistémica (SIRS). En los últimos años el paradigma en enfermedades infecciosas ha cambiado debido a estudios que demuestran como la respuesta inmunitaria del paciente séptico tiene un papel clave en el desarrollo de la enfermedad, con implicaciones en el diagnóstico, pronóstico y tratamiento, que podrían ayudar a cambiar el abordaje en los próximos años gracias a una estrategia basada en medicina de precisión. Hoy los aislamientos microbiológicos y los cultivos siguen siendo el estándar de referencia con varias desventajas como el tiempo para obtener resultados, sobre todo en infecciones por gérmenes resistentes u hongos, que pueden retrasar el inicio de la terapia antimicrobiana. Como alternativa se ha planteado el uso de biomarcadores en sepsis que siendo productos de la respuesta inflamatoria del individuo ante la infección, son útiles para el diagnóstico y pronóstico primordialmente en los críticamente enfermos. Decidimos realizar esta revisión narrativa acerca de la utilidad de los biomarcadores en pacientes con sepsis críticamente enfermos, para enfocarlos en un modelo de medicina personalizada.

Characterization of a novel SCN5A genetic variant A1294G associated with mixed clinical phenotype

Mutations in gene SCN5A, which encodes cardiac voltage-gated sodium channel Nav1.5, are associated with multiple clinical phenotypes. Here we describe a novel A1294G genetic variant detected in a male patient with combined clinical phenotype including atrioventricular II block, Brugada-like ECG, septal fibrosis, right ventricular dilatation and decreased left ventricular contractility. Residue A1294 is located in the IIIS3–S4 extracellular loop, in proximity to several residues whose mutations are associated with sodium channelopathies. The wild-type channel Nav1.5 and mutant Nav1.5-A1294G were expressed in the CHO–K1 and HEK293T cells and whole-cell sodium currents were recorded using the patch-clamp method. The A1294G channels demonstrated a negative shift of steady-state inactivation, accelerated fast and slow inactivation and decelerated recovery from intermediate inactivation. Our study reveals biophysical mechanism of the Nav1.5-A1294G dysfunction, which may underlie the combined phenotypic manifestation observed in the patient.

Severe Asthma and Allergy: A Pediatric Perspective

Severe asthma in children is associated with significant morbidity and lung function decline. It represents a highly heterogeneous disorder with multiple clinical phenotypes. As its management is demanding, the social and economic burden are impressive. Several co-morbidities may contribute to worsen asthma control and complicate diagnostic and therapeutic management of severe asthmatic patients. Allergen sensitization and/or allergy symptoms may predict asthma onset and severity. A better framing of “allergen sensitization” and understanding of mechanisms underlying progression of atopic march could improve the management and the long-term outcomes of pediatric severe asthma. This review focuses on the current knowledge about interactions between severe asthma and allergies.

Plasma levels of pro-inflammatory molecules and their expressions are associated with severity of heart failure: An investigation in Chinese cohort

Heart failure (HF) is a syndrome with multiple clinical phenotypes affecting around 1%–2% of adult population worldwide, and about 230 million Chinese are affected by cardiovascular diseases. The important role of pro-inflammatory plasma cytokines with HF has been demonstrated in different populations. The aim of this study was to investigate importance of pro-inflammatory cytokines in Chinese HF patients. In all, 134 HF patients were enrolled in this study and further classified in to four clinical distinct groups according to New York Heart Association classification criteria (NYHA-I: n = 34, NYHA-II: n = 35, NYHA-III: n = 22 and NYHA-IV: n = 43). Sixty-eight healthy Chinese were enrolled as controls. Plasma levels of tumour necrosis factor-α (TNF-α), TNF-receptor 1 (TNFRI), TNF-receptor 2 (TNFRII), interleukin 6 (IL-6), soluble IL-6 receptor (sIL-6R), C-reactive protein (CRP), soluble cluster of differentiation 14 (sCD14) and interleukin 1 beta (IL-1β) were quantified by enzyme-linked immunosorbent assay (ELISA). Plasma levels of all parameters investigated in this study remained comparable among healthy controls and NYHA-I group. Plasma levels of TNF-α, TNFRI, TNFRII, IL-6, sIL-6R, CRP, sCD14 and IL-1β were significantly higher in NYHA-III and NYHA-IV clinical categories compared to other HF phenotype (NYHA-I and NYHA-II). Interestingly, TNFR-II levels were significantly higher in NYHA-II compared to NYHA-I. No significant difference of plasma sIL-6R was observed among various clinical categories. In conclusion, plasma levels of pro-inflammatory molecules are elevated in severe HF patients and may be used as possible biomarkers for accessing severity of HF.

Manifestations and Management of Difficult-to-Treat Psoriasis

ABSTRACT Psoriasis is a common, immune-mediated skin disorder that can manifest as multiple clinical phenotypes. Although psoriasis affecting the scalp, face, nails, palms, soles, and intertriginous regions has not been studied as extensively as chronic plaque psoriasis in other body areas, these phenotypes can be associated with significant physical, psychosocial, and functional impairments, which impact quality of life. In addition, recent evidence has shown that psoriasis affecting these areas is more prevalent than traditionally thought. In this article, we discuss the clinical characteristics of these hard-to-treat areas and review newer treatment options, which have shown significant efficacy for psoriasis affecting these body regions. To provide optimal care to patients with difficult-to-treat psoriasis, nurses, nurse practitioners, and physician assistants should evaluate patients for scalp, facial, nail, palmoplantar, and inverse psoriasis to provide more effective therapeutic options.

A novel missense mutation in AIFM1 results in axonal polyneuropathy and misassembly of OXPHOS complexes

Apoptosis-inducing factor mitochondrion-associated-1 (AIFM1) in mitochondria has captured a great deal of attention due to its well-described function in apoptosis. Mutations in AIFM1 have resulted in multiple clinical phenotypes, including X-linked Charcot-Marie-Tooth disease type 4. These syndromes usually involve multiple locations within the nervous system and/or multiple organs. This study describes a novel missense mutation in AIFM1 and its associated peripheral nerve disease. Patients with AIFM1 mutation were characterized clinically, electrophysiologically, genetically and by magnetic resonance imaging. The fibroblasts were isolated from the patients to study mitochondrial OXPHOS complexes. We identified a family with a novel missense mutation (Phe210Leu) in AIFM1 who developed an isolated late-onset axonal polyneuropathy in which the central nervous system and other organs were spared. Interestingly, this Phe210Leu mutation resulted in abnormal assembly of mitochondrial complex I and III, and failed to disrupt AIFM1 binding with mitochondrial intermembrane space import and assembly protein 40 (MIA40) in the patients' cells. Deficiency of either AIFM1 or MIA40 is known to impair the assembly of mitochondrial complex I and IV. However, levels of both AIFM1 and MIA40 were unchanged. Phe210Leu mutation in AIFM1 induces an axonal polyneuropathy that might be contributed by the misassembly of mitochondrial complex I and III. This misassembly appears to be independent of the traditional mechanism via AIFM1/MIA40 deficiency.

Functional coding variation in the presynaptic dopamine transporter associated with neuropsychiatric disorders drives enhanced motivation and context-dependent impulsivity in mice

Recent genetic analyses have provided evidence that clinical commonalities associated with different psychiatric diagnoses often have shared mechanistic underpinnings. The development of animal models expressing functional genetic variation attributed to multiple disorders offers a salient opportunity to capture molecular, circuit and behavioral alterations underlying this hypothesis. In keeping with studies suggesting dopaminergic contributions to attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BPD) and autism spectrum disorder (ASD), subjects with these diagnoses have been found to express a rare, functional coding substitution in the dopamine (DA) transporter (DAT), Ala559Val. We developed DAT Val559 knock-in mice as a construct valid model of dopaminergic alterations that drive multiple clinical phenotypes, and here evaluate the impact of lifelong expression of the variant on impulsivity and motivation utilizing the 5- choice serial reaction time task (5-CSRTT) and Go/NoGo as well as tests of time estimation (peak interval analysis), reward salience (sucrose preference), and motivation (progressive ratio test). Our findings indicate that the DAT Val559 variant induces impulsivity behaviors that are dependent upon the reward context, with increased impulsive action observed when mice are required to delay responding for a reward, whereas mice are able to withhold responding if there is a probability of reward for a correct rejection. Utilizing peak interval and progressive ratio tests, we provide evidence that impulsivity is likely driven by an enhanced motivational phenotype that also may drive faster task acquisition in operant tasks. These data provide critical validation that DAT, and more generally, DA signaling perturbations can drive impulsivity that can manifest in specific contexts and not others, and may rely on motivational alterations, which may also drive increased maladaptive reward seeking.

Severe Asthma in Children

Severe asthma in children is associated with significant morbidity and is a highly heterogeneous disorder with multiple clinical phenotypes. Cluster analyses have been performed in several groups to explain some of the heterogeneity of pediatric severe asthma, which is reviewed in this article. The evaluation of a child with severe asthma includes a detailed diagnostic assessment and excluding other possible diagnoses and addressing poor control due to comorbidities, lack of adherence to asthma controller medications, poor technique, and other psychological and environmental factors. Children with severe asthma require significant resources including regular follow-up appointments with asthma education, written asthma action plan, and care by a multidisciplinary team. Management of pediatric severe asthma now includes emerging phenotypic-directed therapies; however, continued research is still needed to further study the long-term outcomes of pediatric severe asthma and its treatment.

Molecular classification of Crohn's disease reveals two clinically relevant subtypes

ObjectiveThe clinical presentation and course of Crohn's disease (CD) is highly variable. We sought to better understand the cellular and molecular mechanisms that guide this heterogeneity, and characterise the cellular...

Bronchopulmonary dysplasia: new becomes old again!

Despite the many advances in neonatology, bronchopulmonary dysplasia (BPD) continues to be a frustrating disease of prematurity. BPD is a disease which is defined oddly by its treatment rather than its pathophysiology, leading to frequently changing nomenclature which has widespread implications on our ability to both understand and follow the progression of BPD. As various treatment modalities for BPD were developed and a larger number of extremely preterm infants survived, the "old" BPD based on lung injury from oxygen therapy and mechanical ventilation transitioned into a "new" BPD focused more on the interruption of normal development. However, the interruption of normal development does not solely apply to lung development. The effects of prematurity on vascular development cannot be overstated and pulmonary vascular disease has become the new frontier of BPD. As we begin to better understand the complex, multifactorial pathophysiology of BPD, it is necessary to again focus on appropriate, pathology-driven nomenclature that can effectively describe the multiple clinical phenotypes of BPD.

Mitochondrial disease: genetics and management.

Mitochondrial disease is one of the most common groups of genetic diseases with a minimum prevalence of greater than 1 in 5000 in adults. Whilst multi-system involvement is often evident, neurological manifestation is the principal presentation in most cases. The multiple clinical phenotypes and the involvement of both the mitochondrial and nuclear genome make mitochondrial disease particularly challenging for the clinician. In this review article we cover mitochondrial genetics and common neurological presentations associated with adult mitochondrial disease. In addition, specific and supportive treatments are discussed.

Measuring the corticosteroid responsiveness endophenotype in asthmatic patients

Inhaled corticosteroids are the most commonly used controller therapies for asthma, producing treatment responses in 6 clinical phenotypes: lung function, bronchodilator response, airway responsiveness, symptoms, need for oral steroids and frequency of emergency department visits and hospitalizations. We hypothesize that treatment response in all of these phenotypes is modulated by a single quantitative corticosteroid responsiveness endophenotype. We sought to develop a composite phenotype that combines multiple clinical phenotypes to measure corticosteroid responsiveness with high accuracy, stability across populations, and robustness to missing data. We used principal component analysis to determine a composite corticosteroid responsiveness phenotype that we tested in 4 replication populations. We evaluated the relative accuracy with which the composite and clinical phenotypes measure the endophenotype using treatment effect area under the receiver operating characteristic curve (AUC). In the study population the composite phenotype measured the endophenotype with an AUC of 0.74, significantly exceeding the AUCs of the 6 individual clinical phenotypes, which ranged from 0.56 (P < .001) to 0.67 (P = .015). In 4 replication populations with a total of 22 clinical phenotypes available, the composite phenotype AUC ranged from 0.69 to 0.73, significantly exceeded the AUCs of 14 phenotypes, and was not significantly exceeded by any single phenotype. The composite phenotype measured the endophenotype with higher accuracy, higher stability across populations, and higher robustness to missing data than any clinical phenotype. This should provide the capability to model corticosteroid pharmacologic response and resistance with increased accuracy and reproducibility.

Proteomic Analysis in CSF Identified Subtype Specific and Shared Molecular Pathways for Multiple Sclerosis Clinical Phenotypes (P5.216)

Proteomic Analysis in CSF Identified Subtype Specific and Shared Molecular Pathways for Multiple Sclerosis Clinical Phenotypes (P5.216)

Identification of Risk Loci for Crohn’s Disease Phenotypes Using a Genome-Wide Association Study

Crohn's disease is a highly heterogeneous inflammatory bowel disease comprising multiple clinical phenotypes. Genome-wide association studies (GWASs) have associated a large number of loci with disease risk but have not associated any specific genetic variants with clinical phenotypes. We performed a GWAS of clinical phenotypes in Crohn's disease. We genotyped 576,818 single-nucleotide polymorphisms in a well-characterized cohort of 1090 Crohn's disease patients of European ancestry. We assessed their association with 17 phenotypes of Crohn's disease (based on disease location, disease behavior, disease course, age at onset, and extraintestinal manifestations). A total of 57 markers with strong associations to Crohn's disease phenotypes (P < 2 × 10(-4)) were subsequently analyzed in an independent replication cohort of 1296 patients of European ancestry. We replicated the association of 4 loci with different Crohn's disease phenotypes. Variants in MAGI1, CLCA2, 2q24.1, and LY75 loci were associated with a complicated stricturing disease course (Pcombined = 2.01 × 10(-8)), disease location (Pcombined = 1.3 × 10(-6)), mild disease course (Pcombined = 5.94 × 10(-7)), and erythema nodosum (Pcombined = 2.27 × 10(-6)), respectively. In a GWAS, we associated 4 loci with clinical phenotypes of Crohn's disease. These findings indicate a genetic basis for the clinical heterogeneity observed for this inflammatory bowel disease.

SPG7 Variant Escapes Phosphorylation-Regulated Processing by AFG3L2, Elevates Mitochondrial ROS, and Is Associated with Multiple Clinical Phenotypes

Mitochondrial production of reactive oxygen species (ROS) affects many processes in health and disease. SPG7 assembles with AFG3L2 into the mAAA protease at the inner membrane of mitochondria, degrades damaged proteins, and regulates the synthesis of mitochondrial ribosomes. SPG7 is cleaved and activated by AFG3L2 upon assembly. A variant in SPG7 that replaces arginine 688 with glutamine (Q688) is associated with several phenotypes, including toxicity of chemotherapeutic agents, type 2 diabetes mellitus, and (as reported here) coronary artery disease. We demonstrate that SPG7 processing is regulated by tyrosine phosphorylation of AFG3L2. Carriers of Q688 bypass this regulation and constitutively process and activate SPG7 mAAA protease. Cells expressing Q688 produce higher ATP levels and ROS, promoting cell proliferation. Our results thus reveal an unexpected link between the phosphorylation-dependent regulation of the mitochondria mAAA protease affecting ROS production and several clinical phenotypes.

α-Synucleinopathy phenotypes

α-Synucleinopathies are neurodegenerative diseases characterised by the abnormal accumulation of α-synuclein aggregates in neurons, nerve fibres or glial cells. While small amounts of these α-synuclein pathologies can occur in some neurologically normal individuals who do not have associated neurodegeneration, the absence of neurodegeneration in such individuals precludes them from having a degenerative α-synucleinopathy, and it has yet to be established whether such individuals have a form of preclinical disease. There are three main types of α-synucleinopathy, Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), with other rare disorders also having α-synuclein pathologies, such as various neuroaxonal dystrophies. Multiple clinical phenotypes exist for each of the three main α-synucleinopathies, with these phenotypes differing in the dynamic distribution of their underlying neuropathologies. Identifying the factors involved in causing different α-synuclein phenotypes may ultimately lead to more targeted therapeutics as well as more accurate clinical prognosis.

Regional Hippocampal Involvement Differs across Multiple Sclerosis Clinical Phenotypes: A Radial Mapping MR-Based Study (PD6.004)

Regional Hippocampal Involvement Differs across Multiple Sclerosis Clinical Phenotypes: A Radial Mapping MR-Based Study (PD6.004)